Kit of parts for treating urinary incontinence in mammals

ABSTRACT

Disclosed are methods for treating urinary incontinence in a mammal wherein a composition comprising a biocompatible polymer, a biocompatible solvent, and a contrast agent is delivered to the periurethral tissue of the mammal.

This application is a CON of Ser. No. 09/848,303, filed on May 4, 2001,now Pat. No. 6,555,104, which was a continuation of U.S. applicationSer. No. 09/269,931, filed on Sep. 27, 1999, now Pat. No. 6,569,417,which is a 371 of PCT/US97/18313, filed Oct. 10, 1997, which is acontinuation of 08/734,016, filed Oct. 18, 1996, now Pat. No. 5,785,642.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

This invention is directed to methods for treating urinary incontinencein mammals generally and humans in particular. In these methods, acomposition comprising a biocompatible polymer, a biocompatible solvent,and a contrast agent is delivered to the periurethral tissue of amammal.

The biocompatible polymer is selected to be soluble in the biocompatiblesolvent, but insoluble in the periurethral tissue. The biocompatiblesolvent is miscible or soluble in the fluids of this tissue and, uponcontact with such fluids, the biocompatible solvent quickly diffusesaway whereupon the biocompatible polymer precipitates to form anocclusion in the periurethral tissue which compresses the urethrathereby preventing or reducing the involuntary leakage of urine from thebladder.

REFERENCES

The following publications are cited in this application as superscriptnumbers:

-   -   ¹ Murless, “The Injection Treatment of Stress Incontinence,” J.        Obstet. Gynaecol., 45: 67-73 (1938).    -   ² Quackels, “Deux Incontinences Après Adénomecomie Guéries Par        Injection de Paraffine Dans Le Périnée,” Acta Urol. Belg., 23:        259-262 (1955).    -   ³ Sachse, “Treatment of Urinary Incontinence with Sclerosing        Solutions: Indications, Results, Complications,” Urol. Int., 15:        225-244 (1963).    -   ⁴ Politano. et al., “Periurethral Teflon Injection for Urinary        Incontinence.” J. Urol., 111: 180-183 (1974).    -   ⁵ Lim, et al., “Periurethral Teflon Injection: A Simple        Treatment for Urinary Incontinence,” Br. J. Urol., 55: 208-210        (1983).    -   ⁶ Schulman, et al., “Endoscopic Injection of Teflon to Treat        Urinary Incontinence in Women,” BMJ, 228: 192 (1984).    -   ⁷ Rodriguez, “Late Results of the Endourethral Injection of        Teflon in Stress Urinary Incontinence,” J. Urol. (Paris), 62:        39-41 (1987).    -   ⁸ Vesey, et al., “Teflon Injection in Female Stress        Incontinence. Effect on Urethral Pressure Profile and Flow        Rate,” Br. J. Urol., 62: 39-41 (1988).    -   ⁹ Smart. “Poltef Paste for Urinary Incontinence,” Aust. N. Z. J.        Surg., 61: 663-666 (1991).    -   ¹⁰ Malizia, et al., “Migration and Granulomatous Reaction After        Periurethral Injection of Polytef (Teflon),” JAMA, 251:        3227-3281 (1984).    -   ¹¹ Stricker, et al., “Injectable Collagen for Type 3 Female        Stress Incontinence: The First 50 Australian Patients,” Med. J.        Aust., 158: 89-91 (1993).    -   ¹² Moore, et al., “Periurethral Implantation of Glutaraldehyde        Cross-Linked Collagen (Contigen®) in Women with Type I or III        Stress Incontinence: Quantitative Outcome Measures,” Br. J.        Urol., 75: 359-363 (1995).    -   ¹³ Capozza, et al., “Endoscopic Treatment of Vesico-Ureteric        Reflux and Urinary Incontinence: Technical Problems in the        Pediatric Patient,” Br. J. Urol., 75: 538-542.(1995).    -   ¹⁴ Atala, et al., “Injectable Alginate Seeded with Chondrocytes        as a Potential Treatment for Vesicoureteral Reflux,” J. Urol.,        150: 745-747 (1993).    -   ¹⁵ Meriguerian, et al., “Submucosal Injection of Polyvinyl        Alcohol Foam in Rabbit Bladder,” J. Urol., 144: 531-533 (1990).    -   ¹⁶ Walker, et al., “Injectable Bioglass as a Potential        Substitute for Injectable Polytetrafluoroethylene,” J. Urol.,        148: 645 (1992).    -   ¹⁷ Atala, et al., “Endoscopic Treatment of Vesicoureteral Reflux        with a Self-Detachable Balloon System,” J. Urol., 148: 724-728        (1992).    -   ¹⁸ Kinugasa, et al., “Direct Thrombosis of Aneurysms with        Cellulose Acetate Polymer”, J. Neurosurg., 77:501-507 (1992).    -   ¹⁹ Kinugasa, et al., “Early Treatment of Subarachnoid Hemorrhage        After Preventing Rerupture of an Aneurysm”, J. Neurosurg.,        83:34-41 (1995).    -   ²⁰ Kinugasa, et al., “Prophylactic Thrombosis to Prevent New        Bleeding and to Delay Aneurysm Surgery”. Neurosurg., 36:661        (1995).    -   ²¹ Greff, et al., U.S. Pat. No. 5,580,568 for “Cellulose        Diacetate Compositions for Use in Embolizing Blood Vessels.    -   ²² Greff, et al., U.S. Pat. No. 5,667,767 for “Novel        Compositions for Use in Embolizing Blood Vessels.    -   ²³ Taki, et al., “Selection and Combination of Various        Endovascular Techniques in the Treatment of Giant Aneurysms”, J.        Neurosurg., 77:37-42 (1992).    -   ²⁴ Park. et al., “New Polymers for Therapeutic Embolization”,        Poster #47, Meeting of Radiological Society of North America        (1993)    -   ²⁵ Winters. et al., “Periurethral Injection of Collagen in the        Treatment of Intrinsic Sphincteric Deficiency in the Female        Patient”, Urologic Clinics of North America, 22(3):473-478        (1995)

All of the above references are herein incorporated by reference intheir entirety to the same extent as if each individual reference wasspecifically and individually indicated to be incorporated herein byreference in its entirety.

State of the Art

Urinary incontinence is an extremely common problem especially in women.In particular, many women suffer from incontinence including stressincontinence. In this condition, the pelvic-floor muscles which supportthe base of the bladder and close off the top of the urethra areweakened by, for example, childbirth or obesity. As a result, whenpressure is exerted on these muscles by coughing, lifting, etc., urineis involuntarily discharged from the bladder through the urethra.

The initial treatment for stress incontinence typically consists ofexercises to strengthen the pelvic-floor muscles. If these exercises areineffective, open surgical repair of the bladder neck is oftenattempted. However, such surgical repair procedures are not successfulfor all patients. Moreover, there are always certain risks associatedwith open surgical procedures, such as trauma, infection, risks ofanesthesia, etc.

As an alternative to surgical repair, urinary incontinence has beentreated by injecting various substances into the tissue surrounding theurethra, i.e., the periurethral tissue, to add bulk to this tissue. Theaim of this treatment is to compress the urethra at the level of thebladder neck thus impeding the involuntary flow of urine from thebladder. Many substances have been tried for this purpose with varyingresults.

For example, Murless has reported the use of sodium morrhuate for thetreatment of stress incontinence.¹ However, this material was notsuccessful in preventing incontinence and pulmonary infarction wasobserved as a complication. Similarly, paraffin² and other sclerosingsolutions³ have been tried with poor results.

More recently, polytetrafluoroethylene particles (TEFLON™, POLYTEF™)have been used as an injectable material for the correction of urinaryincontinence with a success rate of from 30% to 86% in some studies.⁴⁻⁹However, these particles have subsequently been demonstrated to generateforeign body granulomas and to migrate to distant organs, such as thelungs, liver, spleen and brains Accordingly, the use ofpolytetrafluoroethylene particles is currently disfavored.

Another injectable material that has been used recently for thetreatment of urinary incontinence is glutaraldehyde cross-linked bovinedermal collagen. ¹¹⁻¹³ However, a major problem associated with the useof collagen materials is the tendency of the implant to decrease involume over time thereby necessitating retreatment.¹⁴ In addition,collagen has been associated with adverse immune responses and allergicreactions to bovine dermal collagen have been described.¹²

Various other injectable substances have been reported or proposed asimplant materials for the treatment of bladder conditions, such asvesicoureteral reflux. These substances include polyvinyl alcoholfoam,¹⁵ glass particles,¹⁶ a chondrocyte-alginate suspension¹⁴ and adetachable silicone balloon.¹⁷

In addition to the various problems associated with many of thesubstances used to treat urinary incontinence, the methods currentlyemployed for delivering injectable materials to the periurethral tissuehave certain disadvantages. In particular, the amount of materialnecessary to compress the urethra must typically be estimated byobserving the compression of the urethra wall using a cystoscope orendoscope. If an insufficient amount of material is injected in thefirst procedure, top-up injections administered in subsequent proceduresmay be necessary.¹¹ Accordingly, it would be advantageous to be able tomore accurately monitor the size of the occlusion formed by the injectedmaterial to ensure that it is sufficient to block the involuntaryleakage of urine from the bladder. Additionally, if follow-up injectionsare necessary, it would be advantageous to be able to locate accuratelythe site of the material previously injected.

In view of the above, it is evident that there is an ongoing need in theart for new methods of treating urinary incontinence in mammals.Preferably, such methods would allow an occlusion-forming substance tobe delivered accurately to the periurethral tissue. The substanceemployed would preferably conserve its volume in vivo, be non-migratoryand be substantially non-immunogenic.

This invention is directed to the discovery that urinary incontinencecan be treated in mammals by delivering sufficient amounts of acomposition comprising a biocompatible polymer, a biocompatible solvent,and a contrast agent to the periurethral tissue under conditions suchthat a polymer precipitate forms in situ in the periurethral tissue.This polymer precipitate compresses the urethral opening therebyaffording increased outlet resistance and reducing urinary incontinencein the mammal. The polymeric compositions of this invention arenon-biodegradable and, accordingly, do not substantially decrease involume over time. Moreover, the injection process provides for acoherent mass, not particulates, which mass is nonmigratory. Moreover,the contrast agent permits monitoring of the injection by conventionalmethods while it is taking place to ensure that it is being carried outproperly. The contrast agent also allows monitoring post-injection byconventional methods to ensure correct placement of the mass months oreven years after injection. Conventional monitoring methods include, byway of example, fluoroscopy, ultrasound, and in some cases visualdetection.

SUMMARY OF THE INVENTION

This invention is directed to the discovery that unexpected andsurprising results are achieved when mammals with urinary incontinenceare treated with a composition comprising a biocompatible polymer, abiocompatible solvent, and a contrast agent. In particular, deficienciesassociated with the prior art procedures are reduced by the invention.Such deficiencies include, for example, problems associated withmigration of particulates over time, the biodegradation of the injectedmass (e.g., collagen type materials) employed to form an occlusion inthe periurethral tissue of the mammal, problems associated with theaccurate delivery of, such substances, and problems associated withpost-delivery monitoring of the deposited materials.

Accordingly, in one of its method aspects, this invention is directed toa method for treating urinary incontinence in a mammal, which methodcomprises delivering a composition comprising a biocompatible polymer, abiocompatible solvent, and a contrast agent to the periurethral tissueof the mammal

wherein said delivery is conducted under conditions such that a polymerprecipitate forms in situ in the periurethral tissue thereby reducingthe urinary incontinence in the mammal.

In another aspect of this invention, the use of a contrast agent is notrequired and the method is conducted by delivering a compositioncomprising a biocompatible polymer and a biocompatible solvent to theperiurethral tissue of the mammal

wherein said delivery is conducted under conditions such that a polymerprecipitate forms in situ in the periurethral tissue thereby reducing,the urinary incontinence in the mammal.

However, the use of a contrast agent in the composition is preferred.

The methods of this invention are preferably practiced using a kit ofparts comprising:

a first member which is a polymeric composition comprising abiocompatible polymer, a biocompatible solvent and a contrast agent; and

a second member-which is a needle selected from the group selected of apuncture needle and spinal needle.

In the embolic compositions employed herein, the biocompatible polymeris preferably an ethylene vinyl alcohol copolymer or a cellulose acetatepolymer. In a particularly preferred embodiment, the biocompatiblepolymer is selected to be substantially non-immunogenic.

The biocompatible solvent is preferably dimethylsulfoxide and, morepreferably, anhydrous dimethylsulfoxide.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to methods for treating urinary incontinencein mammals, which methods comprise delivering a composition comprising abiocompatible polymer, a biocompatible solvent, and a contrast agent tothe periurethral tissue of the mammal.

Prior to discussing this invention in further detail, the followingterms will first be defined:

The term “urinary incontinence” refers to the involuntary leakage ofurine through the urethra from the bladder. Methods for diagnosingurinary incontinence are well known to those skilled in the relevantart. Such methods included, for example, video urodynamics and pad testsas described by Moore, et al.¹²

The term “periurethral tissue” refers to the tissue surrounding theurethra. As is understood in the art, the urethra is an orifice attachedat its base to the bladder and permits discharge of urine from thebladder. Preferably, the polymeric compositions of the present inventionare delivered to the periurethral tissue at or near the base of theurethra.

The term “biocompatible polymer” refers to polymers which, in theamounts employed, are non-toxic, non-peptidyl, non-migratory, chemicallyinert, and substantially non-immunogenic when used internally in themammal and which are substantially insoluble in the periurethral tissue.The biocompatible polymers do not substantially decrease in volume overtime and, since the polymer forms a solid inert mass, it does notmigrate to distant organs within the body. Suitable biocompatiblepolymers include, by way of example, cellulose acetates¹⁸⁻²⁰ (includingcellulose diacetate²¹), ethylene vinyl alcohol copolymers²²⁻²³,polyalkyl(C₁-C₆) acrylates, polyalkyl alkacrylates wherein the alkyl andthe alk groups contain no more than 6 carbon atoms, polyacrylonitrileand the like. Additional biocompatible polymers are disclosed in U.S.patent application Ser. No. 08/655,822 entitled “Novel Compositions forUse in Embolizing Blood Vessels” which application is incorporatedherein by reference in its entirety. Further examples of biocompatiblepolymers are provided by Park, et al.²⁴ Preferably, the biocompatiblepolymer is also non-inflammatory when employed in vivo.

The particular biocompatible polymer employed is not critical and isselected relative to the viscosity of the resulting polymer solution,the solubility of the biocompatible polymer in the biocompatiblesolvent, and the like. Such factors are well within the skill of theartisan.

Preferably, the biocompatible polymers do not appreciably absorb waterupon contact with the fluid of the periurethral tissue and typicallywill have an equilibrium water content of less than about 25% water andpreferably less than about 15% water.

Particularly preferred biocompatible polymers include cellulosediacetate and ethylene vinyl alcohol copolymer. Cellulose diacetatepolymers are either commercially available or can be prepared byart-recognized procedures. In a preferred embodiment, the number averagemolecular weight, as determined by gel permeation chromatography, of thecellulose diacetate composition is from about 25,000 to about 100,000;more preferably from about 50,000 to about 75,000; and still morepreferably from about 58,000 to 64,000. The weight average molecularweight of the cellulose diacetate composition, as determined by gelpermeation chromatography, is preferably from about 50,000 to 200,000and more preferably from about 100,000 to about 180,000. As is apparentto one skilled in the art, with all other factors being equal, cellulosediacetate polymers having a lower molecular weight will impart a lowerviscosity to the composition as compared to higher molecular weightpolymers. Accordingly, adjustment of the viscosity of the compositioncan be readily achieved by mere adjustment of the molecular weight ofthe polymer composition.

Ethylene vinyl alcohol copolymers comprise residues of both ethylene andvinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent)of additional monomers can be included in the polymer structure orgrafted thereon provided such additional monomers do not alter theocclusion-forming properties of the composition. Such additionalmonomers include, by way of example only, maleic anhydride, styrene,propylene, acrylic acid, vinyl acetate, and the like.

Ethylene vinyl alcohol copolymers are either commercially available orcan be prepared by art-recognized procedures. Preferably, the ethylenevinyl alcohol copolymer composition is selected such that a solution of6 weight percent of the ethylene vinyl alcohol copolymer, 35 weightpercent of a tantalum contrast agent in DMSO has a viscosity equal to orless than 60 centipoise at 20° C. As is apparent to one skilled in theart, with all other factors being equal, copolymers having a lowermolecular weight will impart a lower-viscosity to the composition ascompared to higher molecular weight copolymers. Accordingly, adjustmentof the viscosity of the composition as necessary for catheter or needledelivery can be readily achieved by mere adjustment of the molecularweight of the copolymer composition.

As is also apparent, the ratio of ethylene to vinyl alcohol in thecopolymer affects the overall hydrophobicity/hydrophilicity of thecomposition which, in turn, affects the relative solubility of thecomposition in the biocompatible solvent as well as the rate ofprecipitation of the copolymer in an aqueous solution (e.g., plasma). Ina particularly preferred embodiment, the copolymers employed hereincomprise a mole percent of ethylene of from about 25 to about 60 and amole percent of vinyl alcohol of from about 40 to about 75. Morepreferably, these copolymers comprise from about 40 to about 60 molepercent of vinyl alcohol and from about 60 to 40 mole percent ofethylene. These compositions provide for requisite precipitation ratessuitable for treating urinary incontinence in mammals.

The term “contrast agent” refers to a biocompatible (non-toxic)radiopaque material capable of being monitored during injection into amammalian subject by, for example, radiography. The contrast agent canbe either water soluble or water insoluble, Examples of water solublecontrast agents include metrizamide, iopamidol, iothalamate sodium,iodomide sodium, and meglumine. Examples of water insoluble contrastagents include tantalum, tantalum oxide, and barium sulfate, each ofwhich is commercially available in the proper form for in vivo useincluding a particle size of about 10 μm or less. Other water insolublecontrast agents include gold, tungsten, and platinum powders.

Preferably, the contrast agent is water insoluble (i.e., has a watersolubility of less than 0.01 mg/ml at 20° C.).

The term “biocompatible solvent” refers to an organic material liquid atleast at body temperature of the mammal in which the biocompatiblepolymer is soluble and, in the amounts used, is substantially non-toxic.Suitable biocompatible solvents include, by way of example,dimethylsulfoxide, analogues/homologues of dimethylsulfoxide, ethanol,acetone, and the like. Aqueous mixtures with the biocompatible solventcan also be employed provided that the amount of water employed issufficiently small that the dissolved polymer precipitates upon contactwith the periurethral tissue. Preferably, the biocompatible solvent isdimethylsulfoxide.

Compositions

The polymer employed in the methods of this invention are prepared byconventional methods whereby each of the components is added and theresulting composition mixed together until the overall composition issubstantially homogeneous.

For example, polymer compositions can be prepared by adding sufficientamounts of the biocompatible polymer to the biocompatible solventto-achieve the effective concentration for the polymer composition.Preferably, the polymer composition will comprise from about 2.5 toabout 8.0 weight percent of the biocompatible polymer based on the totalweight of the polymer composition, including contrast agent andbiocompatible solvent, and more preferably from about 4 to about 5.2weight percent. If necessary, gentle heating and stirring can be used toeffect dissolution of the biocompatible polymer into the biocompatiblesolvent. e.g., 12 hours at 50° C.

Sufficient amounts of the contrast agent are then added to the -solutionto achieve the effective concentration for the complete polymercomposition. Preferably, the polymer composition will comprise fromabout 10 to about 40 weight percent of the contrast agent and morepreferably from about 20 to about 40 weight percent and even morepreferably about 35 weight percent each based on the total weight of thepolymer composition including the biocompatible polymer and thebiocompatible solvent. When the contrast agent is not soluble in thebiocompatible solvent, stirring is employed to effect homogeneity of theresulting suspension. In order to enhance formation of the suspension,the particle size of the contrast agent is preferably maintained atabout 10 μm or less and more preferably at from about 1 to about 5 μm(e.g., an average size of about 2 μm). In one preferred embodiment, theparticle size of a water insoluble contrast agent is prepared, forexample, by fractionation. In such an embodiment, a water insolublecontrast agent such as tantalum having a particle size of less thanabout 20 microns is added to an organic liquid such as ethanol(absolute) preferably in a clean environment. Agitation of the resultingsuspension followed by settling for approximately 40 seconds permits thelarger particles to settle faster. Removal of the upper portion-of theorganic liquid followed by separation of the liquid from the particlesresults in a reduction of the particle size which is confirmed under amicroscope. The process is optionally repeated until a desired particlesize is reached.

The particular order of addition of components to the biocompatiblesolvent is not critical and stirring of the resulting suspension isconducted as necessary to achieve homogeneity of the composition.Preferably, mixing/stirring of the composition is conducted under ananhydrous atmosphere at ambient pressure. The resulting composition maybe heat sterilized and then stored preferably in sealed bottles (e.g.,amber vials) or vials until needed.

Methods

The compositions described above are then employed in methods fortreating urinary incontinence in mammals. In these methods, thecomposition is introduced to the periurethral tissue via conventionalcatheter or needle technology using, for example, cystoscopictechniques. Specifically, the injection may be performed through apuncture needle or spinal needle placed directly through the cystoscopeor periurethrally with a spinal needle placed percutaneously at theintroitus and positioned in the tissue adjacent to the urethra asdescribed by Winters, et al.²⁵ Alternatively, the periurethral tissuecan be exposed surgically and the composition injected directly into thetissue.

Upon discharge of the composition from the catheter or the needle intothe periurethral tissue, the biocompatible solvent dissipates into thefluid of the periurethral tissue resulting in the precipitation of thebiocompatible polymer which precipitate forms a coherent mass. Theformed precipitate in the periurethral tissue swells this tissuerestricting the urethral orifice thus impeding the involuntary flow ofurine from the bladder.

The particular amount of polymer composition employed is dictated by thelevel of pre-existing support of the periurethral tissue, theconcentration of polymer in the composition, the rate of precipitation(solids formation) of the polymer, etc. Such factors are well within theskill of the artisan. For example, individuals with weak pre-existingsupport of the periurethral tissue will require injection of morepolymer composition in order to bulk up this tissue and constrict theurethra as compared to individuals with stronger pre-existing support.

The methods of this invention are particularly advantageous because thepresence of the contrast agent in the composition permits, if desired,monitoring of the delivery of the biocompatible polymer while it istaking place either by fluoroscopy, ultrasound, or visually. In thisway, one can ensure that the biocompatible polymer is being delivered tothe optimal location in the periurethral tissue as well as determinewhether the size of the polymer precipitate thus-formed will besufficient to block the involuntary leakage of urine from the bladder.

Moreover, the treatment process can be modified by altering the rate ofprecipitation of the polymer which can be controlled merely by changingthe overall hydrophobicity/hydrophilicity of the polymer. As isunderstood in the art, faster precipitation rates are achieved by a morehydrophobic polymer composition.

When delivery of the polymeric composition to the periurethral tissue isconducted via a cystoscope used in combination with a small diametermedical catheter (which typically employs a needle as described byCapozza, et al.¹³), the catheter employed is not critical provided thatpolymeric catheter components are compatible with the polymericcomposition (i.e., the catheter components will not readily degrade inthe polymer composition and none of the components of the polymercompositions will readily degrade in the presence of the cathetercomponents). In this regard, it is preferred to use polyethylene in thecatheter components because of its inertness in the presence of thepolymeric composition described herein. Other materials compatible withthe composition can be readily determined by the skilled artisan andinclude, for example, other polyolefins, fluoropolymers (e.g.,polytetrafluoroethylene, perfluoroalkoxy resin, fluorinated ethylenepropylene polymers), silicone, etc.

When introduced into the periurethral tissue, the biocompatible solventrapidly diffuses into the fluids of this tissue leaving a solidprecipitate. The precipitate is a coherent mass comprising a combinationof the biocompatible polymer and the contrast agent. Without beinglimited to any theory, it is believed that this precipitate bulks up theperiurethral tissue thereby increasing outlet resistance to urinary flowfrom the bladder. This enhanced outlet resistance reduces the urinaryincontinence in the treated mammal.

Another advantage of this invention is that the precipitate forms acoherent mass which is substantially retained at the site of injectionthereby obviating prior art concerns with migration of injectedparticulates into the periurethral tissue. Moreover, the polymericcompositions of this invention are non-biodegradable and, accordingly,do not substantially decrease in volume over time.

Still another advantage of this invention is that the polymer employedcan be selected to be non-immunogenic thereby obviating concerns raisedby use of collagen-type materials which can produce an immune responsein vivo.

Yet another advantage of this invention is the formation of a polymericmass in the periurethral tissue which mass contains a water insolublecontrast agent that permits the physician to monitor the implant overtime to assure proper retention of the mass in the tissue. Additionally,if a subsequent injection is necessary to further reduce urinaryincontinence in the mammal, placement of the additional polymericmaterial is facilitated when the material previously implanted can bevisualized by, for example, fluoroscopy, ultrasound, and the like. Asubsequent injection can occur at any time after the initial injectionincluding, for example, months or years later.

In view of the above, the methods of this invention are preferablypracticed using a kit of parts which kit contains a first member whichis a polymeric composition comprising a biocompatible polymer, abiocompatible solvent and a contrast agent, and a second member which isa needle selected from the group consisting from a puncture needle andspinal needle.

Utility

The methods described herein are useful in treating mammals with urinaryincontinence. Accordingly, these methods find use in human and othermammalian subjects requiring such treatment.

Additionally, it is contemplated that the compositions of this inventioncan be used to treat vesicoureteral reflux in a mammal. In thiscondition, urine from the bladder refluxes into a ureter often causinginfection. It is contemplated the such reflux can be treated bydelivering a composition comprising a biocompatible polymer, abiocompatible solvent, and a contrast agent to the subureteral tissue ofthe mammal. This delivery would be conducted under conditions such thata polymer precipitate forms in situ in the subureteral tissue therebyreducing vesicoureteral reflux in the mammal. The formation of a polymerprecipitate in the subureteral tissue is expected to compress the ureterthereby reducing the reflux of urine into the ureter. Methods fordelivering the composition to treat vesicoureteral reflux are describedby Capozza, et al.¹³

The following examples are set forth to illustrate the claimed inventionand are not to be construed as a limitation thereof.

EXAMPLES

Unless otherwise stated, all temperatures are in degrees Celsius. Also,in these examples and elsewhere, the following abbreviations have thefollowing meanings:

cc = cubic centimeter DMSO = dimethylsulfoxide EVOH = ethylene vinylalcohol copolymer mL = milliliter mm = millimeter μm = micron

In the following examples, Examples 1-2 illustrate the preparation ofpolymer compositions useful in the methods described herein whichpolymer compositions comprise EVOH and cellulose acetate. Example 3demonstrates the biocompatibility, non-migratory and bulking propertiesof an EVOH polymer in vivo.

Example 1

An EVOH polymer composition was prepared by combining 8 grams of EVOH(44 mole percent ethylene), 30 grams of tantalum having an averageparticle size of about 3 μm (narrow size distribution), and 100 mL ofanhydrous DMSO. Heating at about 50° C. for about 12 hours was used toaid dissolution. The composition was mixed until homogeneous.

Tantalum having an average particle size of about 3 μm (narrow sizedistribution) was prepared by fractionation wherein tantalum, having anaverage particle size of less than about 20 μm, was added to ethanol(absolute) in a clean environment. Agitation of the resulting suspensionwas followed by settling for approximately 40 sec. to permit the largerparticles to settle faster. Removal of the upper portion of the ethanolfollowed by separation of the liquid from the particles results in areduction of the particle size which is confirmed under a microscope(Nikon Alphaphot™). The process was repeated, as necessary, until anaverage 3 μm particle size was reached.

Example 2

A cellulose diacetate polymer composition is prepared by combining 8grams of cellulose acetate (39.7 weight percent acetyl content), 30grams of tantalum having an average particle size of about 3 μm (narrowsize distribution), and 100 mL of DMSO. The composition is mixed untilhomogeneous. Tantalum having an average particle size of about 3 μm(narrow size distribution) is prepared by fractionation as described inExample 1.

Example 3

The purpose of this example is to demonstrate the biocompatibility of anEVOH polymer with the bladder tissue of a mammal and to illustrate thenon-migratory properties of such a polymer. Additionally, this exampleillustrates the ability of such a polymer to serve as a bulking agent inbladder tissue.

Female New Zealand white rabbits were utilized for this investigation.Using a 26 gauge needle, several 0.5 cc injections of an EVOH polymercomposition, prepared in a manner essentially the same as that describedin Example 1, were made submucosally in the bladder of each rabbit whilethe animals were under general anesthesia. Prior to sacrifice, x-rayswere obtained to search for migration of the injected material. Tworabbits were sacrificed at one week post-injection and the bladdersexcised and examined histologically via 5 micron sectioning/staining offresh-frozen and paraffin embedded tissue samples of the injection sitesand surrounding areas. The injection sites showed black pigmentation(tantalum) with some inflammation and cellular infiltration, i.e., atypical foreign body reaction. Tissues surrounding the injection sitewere normal. The implant had not migrated and appeared as one coherentmass.

From the foregoing description, various modifications and changes in thecomposition and method will occur to those skilled in the art. All suchmodifications coming within the scope of the appended claims areintended to be included therein.

1. A kit of parts suitable for treating urinary incontinence in a human,which kit comprises: a first member which comprises a compositioncomprising a biocompatible solvent and a biocompatible polymer whichpolymer is insoluble in the periuretheral tissue and which is dissolvedin said biocompatible solvent, wherein said polymer has a waterequilibrium content of less than 25% water; a second member whichcomprises a needle selected from a puncture needle and a spinal needle.2. The kit of parts according to claim 1, wherein said biocompatiblepolymer is selected from the group consisting of cellulose acetatepolymers, ethylene vinyl alcohol copolymers, and polyacrylates.
 3. Thekit of parts according to claim 2, wherein said biocompatible polymer isselected from the group consisting of cellulose acetate polymers andethylene vinyl alcohol copolymers.
 4. The kit of parts according toclaim 1, wherein said biocompatible solvent is dimethylsulfoxide.